Hydroxy-acetylene-substituted cyclohexenone

ABSTRACT

A total synthesis of canthaxanthin or dinor-canthaxanthin, known food coloring agents, from pentols.

SUMMARY OF THE INVENTION

In accordance with this invention, a method is provided for synthesizinga compound of the formula: ##STR1## wherein n is an integer of from 0to 1. The compound of formula I where n is 1 in canthaxanthin which hasthe following formula: ##STR2## which, in accordance with thisinvention, can be prepared from either 3-pentol which has the formula:##STR3## or a 1-pentol which has the formula: ##STR4## via condensationwith a compound of the formula: ##STR5## wherein R is an alkyl groupcontaining 3 to 8 carbon atoms; OR CONDENSATION WITH A COMPOUND OF THEFORMULA: ##STR6##

The compound of formula I where n is 0 is dinor-canthaxanthin and hasthe formula: ##STR7##

This compound can also be prepared from the compound of formula II-B bycondensation with a compound of the formula: ##STR8## wherein R is asabove.

DETAILED DESCRIPTION

The term "halogen" as used throughout this specification includes allfour halogens, i.e., chlorine, fluorine, bromine and iodine. The term"lower alkyl" as used herein designates a saturated aliphatic straightor branched chain hydrocarbon containing from 1 to 7 carbon atoms suchas ethyl, methyl, isopropyl, etc. The term "lower alkoxy" as usedthroughout the specification denotes lower alkoxy groups containing from1 to 7 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, etc.

As used herein, the term "aryl" designates mononuclear aromatichydrocarbon groups such as phenyl, tolyl, which can be unsubstituted orsubstituted in one or more positions with a halogen, nitro, lower alkylor lower alkoxy substituent and polynuclear aryl groups such asnaphthyl, anthryl, phenanthryl, which can be unsubstituted orsubstituted with one or more of the aforementioned groups. The preferredaryl groups are the substituted and unsubstituted mononuclear groupsparticularly phenyl. The term "alkali metal" includes all alkali metalssuch as sodium, potassium and lithium.

Dinor-canthaxanthin may be utilized as a food coloring agent in the samemanner as canthaxanthin.

In accordance with a preferred embodiment of this invention, thecompound of formula I is produced from a compound of formula II-B byfirst protecting the free hydroxy group with a hydrolyzable ether moietyto form a compound of the formula: ##STR9## wherein R₁ is hydrogen ortaken together with its attached oxygen moiety forms an ether protectinggroup removable by hydrolysis.

In accordance with this preferred embodiment of this invention, OR₁ mayform an ether which upon hydrolysis yields the hydroxy group. Among theether protecting groups are included the tetrahydropyranyl, lower alkylor 4-methyl-5,6 -dihydro-2H-pyranyl ether. Other ether groups includearylmethyl ethers such as benzyl, benzylhydryl, or trityl ethers as wellas alpha-lower alkoxy-lower alkyl ethers such as methoxymethyl ethers,or methoxy ethyl ether. Among the preferred ether groups are t-butyl,benzyl and the alpha-lower alkoxylower alkyl ether groups. However, thisreaction can take place where the hydroxy in the compound of formulaII-B is free.

The compound of formula VI is converted to the compound of formula I viathe following intermediates:

    ______________________________________                                         ##STR10##                    VIII                                             ##STR11##                    IX                                               ##STR12##                    X                                                ##STR13##                    XI                                               ##STR14##                    XII                                             wherein X is halogen, R.sub.1 is as above; R.sub.5, R.sub.6 and R.sub.7 are     aryl or lower alkyl.

The compound of formula II-B is converted to the compound of formula VIutilizing any conventional method of etherifying a hydroxy group. Wherethe preferred ether group is an alpha-lower alkoxylower alkyl group, thecompound of formula II-B is reacted with a vinyl ether of the formula:##STR15## wherein R₈ and R₉ are lower alkyl. This reaction is carriedout in the presence of an acid catalyst. Any conventional acid catalystcan be utilized. Among the preferred acid catalysts are the strongorganic acids such as p-toluene sulfonic acid or inorganic mineral acidssuch as sulfuric acid, hydrochloric acid, etc. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature and atmospheric pressure. Ifdesired, higher and lower temperatures can be utilized.

The compound of formula VI is converted to the compound of formula VIIIby reacting the compound of formula VI with a compound of the formula:##STR16## In this reaction, the compound of formula VI is in thefollowing form: ##STR17## wherein Y is MgX or an alkali metal; and R₁ isas above.

The compound of formula VI-B is formed from the compound of formula VIutilizing any conventional method of forming either a Grignard salt oran alkali metal acetylide. For example, the alkali metal acetylide saltof formula VI can be formed by reacting the compound of formula VI withan alkali metal lower alkyl such as n-butylithium in an ether solvent attemperatures of -80° C. to -20° C.

The reaction of the compound of formula VI-B with the compound offormula III to produce a compound of the formula VIII is carried oututilizing conventional Grignard conditions. Any of the conditionsconventional in Grignard reactions can be utilized in carrying out thisreaction. Among the preferred conditions for carrying out this reactionis utilizing an inert organic solvent medium. Any conventional inertorganic solvent medium can be utilized. Among the preferred solvents arethe ether solvents such as diethyl ether, tetrahydrofuran, etc. Othersolvents which can be utilized are the hydrocarbon solvents such asbenzene, toluene, etc. In general, this reaction can be carried out atroom temperature and atmospheric pressure. On the other hand, elevatedor reduced temperatures can be utilized. Generally, it is preferred tocarry out this reaction at a temperature of from -50° C. to +50° C.

Where R₁ is an ether protecting group, the compound of formula VIII canbe coverted to the compound of formula IX by conventional etherhydrolysis. Any method conventionally utilized to cleave ether groupscan be utilized to carry out this conversion. Among the preferredmethods is to treat the compound of formula VIII with an aqueousinorganic acid such as dilute hydrochloric acid, dilute sulfuric acid,etc. Generally, this reaction is carried out in an aqueous medium. Incarrying out this reaction, temperature and pressure are not criticaland this reaction can be carried out at room temperature and atmosphericpressure.

The compound of formula IX is converted to the compound of formula X bypartially hydrogenating the compound of formula IX. Any conventionalmethod of partial hydrogenation can be utilized in carrying out thisreaction. Generally, this reaction is carried out by hydrogenating inthe presence of a selective hydrogenation catalyst, e.g., a palladiumlead catalyst in the presence of quinoline, of the type disclosed inHelvetica Chemica Acta; 35 446 (1952). The selective hydrogenation ofthe triple bond of the compound of formula IX when converted to thecompound of formula X produces a double bond at the 1,2 position of thecompound of formula X having a trans configuration.

The compound of formula X is converted to the compound of formula XI bytreating the compound of formula X with a halogenating agent. Any of theconditions conventional in halogenating an alcohol can be utilized tocarry out this reaction. Among the conventional halogenating agentswhich can be utilized are included phosphorous tribromide, triphenylphosphine dibromide and thionyl chloride. Any of the conditionsconventional in utilizing these halogenating agents can be used toconvert the compound of formula X to the compound of formula XI.

The compound of formula XI is converted to the compound of formula XIIby treating the compound of formula XI with a phosphine or treating thecompound of formula X with an acid addition salt of a phosphine. Anymethod conventional in forming phosphonium salts can be utilized in thisconversion.

The compound of formula I is formed from the compound of formula XII byreacting the compound of formula XII with a compound of the formula:##STR18## via a Wittig reaction.

This reaction is carried out utilizing conditions that are conventionalin Wittig type reactions. In this reaction, two moles of the compound offormula XII are reacted per mole of the compound of formula XIII.

Where the 1-pentol of formula II-B has a trans configuration about thedouble bond contained therein, this trans configuration is carried outthrough this synthesis to its conversion to the compound of formula I.Hence, compounds of formula VIII and formula IX produced thereby have atrans configuration about the double bond. The compound of formula IXhaving the trans configuration is converted to the compound of formula Iwith this same trans configuration intact. On the other hand, where thecompound of formula II-B has a cis configuration, this cis configurationis maintained about this double bond throughout the conversion of thecompound of the formula II-B to the compound of formula I. The compoundof formula I which contains cis double bonds can be directly isomerisedto the compound of formula I having an all trans configuration byconventional methods such as heating in water or in an organic solventmedium.

The compound of formula III-A can be prepared via the reaction of acompound of the formula: ##STR19## wherein R₁₀ is lower alkyl; with acompound of the formula: ##STR20## to produce a compound of the formula:##STR21## wherein R₁₀ is as above.

The compound of formula XIV is reacted with the compound of formula XVto produce a compound of the formula XVI by Michael addition. Generally,this reaction is carried out in the presence of an alkali metal amidesuch as the alkali metal lower alkyl amide. Among the preferred amidesare sodiumdiethylamide, lithiumdiisopropylamide, etc. Generally, thisreaction is carried out in an inert solvent. Any conventional inertsolvent can be utilized. Among the preferred solvents are the ethersolvents such as dioxane, tetrahydrofuran, etc. In general, the alkalimetal alkyl amides can be generated in the reaction medium by adding analkali metal alkyl or phenyl and an alkyl amine.

Any conventional alkyl amine such as the lower alkyl amines and anyconventional alkali metal lower alkyl can be utilized in this reaction.Among the preferred alkyl amines are included ethyl amine, n-butyl amineand diisopropyl amine. Among the preferred alkali metal lower alkyls orphenyls are included n-butyl lithium, n-phenyl sodium. This reaction canbe carried out at temperatures of from -120° C. to -60° C.

The compound of formula XVI is converted to the compound of formulaIII-A via the following intermediate: ##STR22##

The compound of formula XVI is converted to the compound of formula XVIIby treating the compound of the formula XVI with an alkali metal hydridesuch as sodium hydride. Generally, this reaction is carried out in aninert organic solvent. Any conventional inert organic solvent can beutilized. Among the preferred inert organic solvents are the ethersolvents such as diethyl ether, tetrahydrofuran, etc. Generally, thisreaction is carried out by refluxing the compound of formula XVI in thepresence of the alkali metal hydride in the ether solvent. Dependingupon the ether solvent, the refluxing can be carried out at atemperature of from 35° C. to 80° C.

The compound of formula XVII is converted to the compound of formulaIII-A by etherifying the compound of formula III-A. Any conventionalmethod of etherifying can be utilized to carry out this reaction.Generally the etherification is carried out by treating the compound offormula XVII with a lower alkanol containing from about 3 to 7 carbonatoms. Generally, it is preferred to utilize lower alkanols containing 3to 7 carbon atoms since they preferentially etherify one of the two oxogroups to produce a compound of formula III-A. Generally, this reactionis carried out by condensing the alcohol with the compound of formulaXVII in the presence of an acid catalyst. Any conventional acid catalystcan be utilized. Among the preferred acid catalysts are p-toluenesulfonic acid and acid forms of ion exchange resins. This reaction canbe carried out by removing the water formed from the reaction. Anyconventional method for removing the water formed during this reactioncan be utilized. Among the preferred methods for removing water is byazeotropic distillation utilizing solvents which form an azeotrope suchas benzene, toluene, xylene as well as other aromatic hydrocarbonsolvents. Any conventional method of azeotropic distillation can beutilized to carry out this procedure. Where water is formed byazeotropic distillation, the reaction is generally carried out in anyconventional solvent capable of forming an azeotrope with water.Furthermore, in this case, the reaction is carried out at the refluxtemperature of the azeotropic mixture.

The compound of formula III-B is prepared from a compound of theformula: ##STR23## via an intermediate of the formula: ##STR24## whereinR is as above. The compound of formula XVIII is converted to thecompound of formula XIX in the same manner as described in connectionwith the conversion of a compound of the formula XVII to a compound offormula III-A.

The compound of formula XIX is converted to a compound of formula III-Bby treating the compound of formula XIX with an alkali metal alkyl amideand a metal halide. In carrying the process of this invention, thealkali metal lower alkyl amides are generally preferred. Among thesealkali metal lower alkyl amides, diisopropyl lithium amide isparticularly preferred. In carrying out this reaction, two moles of themethyl halide are reacted with one mole of the compound of formula XIX.Generally, this reaction is carried out in an inert organic solvent. Anyconventional inert organic solvent can be utilized. Among the preferredsolvents are included ether solvents such as diethyl ether,tetrahydrofuran, etc. This reaction is carried out at temperatures offrom about -80° C. to about 30° C., with temperatures of from about -70°C. to about 40° C. being preferred.

In accordance with another embodiment of this invention, the compound offormula I-A can be prepared from a compound of formula II-A via thefollowing intermediates;

    __________________________________________________________________________     ##STR25##                                                XXI                  ##STR26##                                                XXII                 ##STR27##                                                XXIII                ##STR28##                                                XXIV                 ##STR29##                                                XXV                  ##STR30##                                                XXVI                 ##STR31##                                                XXVII                ##STR32##                                                XXVIII                 wherein X, R.sub.1, R.sub.5, R.sub.6 and R.sub.7 are as above and     R.sub.11 is lower alkanoyl.

The compound of formula II-A is converted to the compound of the formulaXXI by etherification in the manner described in connection with theconversion of the compound of the formula II-B to the compound of theformula VI. In carrying out this reaction, any conventional method ofetherifying a hydroxy group can be utilized. The preferred ether groupformed by R₁ is an alpha-lower alkoxy lower alkyl ether and it is formedin the same manner described in connection with the formation of acompound of the formula VI.

The compound of the formula XXI is reacted with2,6,6-trimethylcyclohexen-2-en-1-one utilizing a magnesium halide oralkali metal salt of the compound of the formula XXI. This reaction iscarried out utilizing conventional Grignard conditions.

The compound of formula XXII is converted to the compound of the formulaXXIII by treating with a lower alkanoic acid, preferably acetic acid. Incarrying out this reaction, the lower alkanoic acid is utilized as thesolvent medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out under roomtemperature and atmospheric pressure. If desired, higher or lowertemperatures can be utilized. In general, the reaction is carried out atfrom about 10° C. to 70° C.

The compound of formula XXIII is converted to the compound of theformula XXIV utilizing basic hydrolysis. Any conventional method ofbasic hydrolysis can be utilized to carry out this conversion. Generallyit is preferred to treat the compound of formula XXIV in an aqueousmedium with an alkali metal hydroxide such as potassium or sodiumhydroxide. In carrying out this hydrolysis reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, elevated orreduced temperature can be utilized.

The compound of the formula XXIV is converted to the compound of formulaXXV by oxidation with chromium trioxide or manganese dioxide. Any of theconditions conventional in oxidizing with these oxidizing agents can beutilized to carry out this conversion.

On the other hand, the compound of formula XXV can be formed from thecompound of formula XXI by first converting the compound of formula XXIto a compound of the formula: ##STR33## wherein Y and R₁ are as above;and reacting the compound of formula XXI-A with a compound of theformula III-A to form an intermediate of the formula: ##STR34## whereinR₁ is as above.

The compound of formula XXI is converted to the compound of formulaXXI-A in the same manner as described in connection with the conversionof a compound of the formula VI to a compound of the formula VI-B. Thereaction of the compound of the formula XXI-A with a compound of theformula III-A is carried out in the same manner as describedhereinbefore in connection with the reaction of a compound of theformula III with a compound of the formula VI-B to form a compound ofthe formula VIII. The reaction of the compound of the formula XXI-A witha compound of the formula III-A forms the compound of the formula XXIX.Where R₁ forms an ether protecting group, the compound of the formulaXXIX is converted by acid hydrolysis to form the compound of the formulaXXV. This acid hydrolysis can be carried out by treating the compound ofthe formula XXIX with an organic or mineral acid. This hydrolysis iscarried out in the same manner as described in connection with theconversion of the compound of the formula VIII to a compound of theformula IX.

The compound of the formula XXV is converted to a compound of theformula XXVI by treating the compound of the formula XV with ahalogenating agent in the same manner as described hereinbefore inconnection with the conversion of a compound of the formula X to acompound of the formula XI. The compound of the formula XXVI isconverted to the compound of the formula XXVII by forming the phosphinesalt in the same manner as described in connection with the conversionof a compound of the formula XI with a compound of the formula XII. Thecompound of the formula XXVII can be reacted via a Wittig reaction witha compound of the formula: ##STR35## to produce a compound of theformula XXVIII. This reaction is carried out in the same manner asdescribed in connection with the conversion of a compound of the formulaXII to a compound of the formula I. The compound of formula XXVIII isconverted by selective hydrogenation to the compound of formula I-A.This reaction is carried out in the same manner as described inconnection with the conversion of the compound of the formula IX to acompound of the formula X.

The following Examples are illustrative but not limitative of thepresent invention. All temperatures are in degrees Centigrade (° C.) andthe ether utilized is diethyl ether.

The term "concentrated aqueous hydrochloric acid" designates 10 or moremolar hydrochloric acid. The term "Lindlar catalyst" designated acatalyst prepared from palladium chloride, calcium carbonate and leadacetate as described in Organic Synthesis Collective Volume 5, page880-893 (1973).

EXAMPLE 1 1-Ethoxy-1-(3-methyl-4-trans-penten-1-yn-1-oxy)ethane

Ethyl vinyl ether (35 ml) was cooled to 5° and treated withp-toluenesulfonic acid (PTSA; monohydrate; 100 mg) followed by the slowaddition of freshly distilled 3-methyl-2-trans-penten-4-yn-1-ol (> 95%trans; 20g). After the exothermic reaction had subsided the mixture wasleft at room temperature for 10 min., quenched with triethylamine (.5ml) and distilled to yield1-ethoxy-1-(3-methyl-4-trans-penten-1-yn-1-oxy)ethane (32.1g) bp 44°-45°C.

EXAMPLE 2

By reacting ethyl vinyl ether with 3-methyl-4-penten-1-yn-3-ol in themanner of Example 1, the compound1-ethoxy-1-[3-methyl-4-penten-1-yn-3-oxy]ethane was produced.

EXAMPLE 31-Ethoxy-[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane

The compound 1-ethoxy-1-[3-methyl-4-penten-1-yn-3-oxy] ethane (3.4g) wasdissolved in diethyl ether (30 ml), cooled to -60°, treated with asolution of n-butyllithium (10.6 ml; 1.9M in hexane), warmed to 0°, andstirred for 5 min. This clear solution of the lithium salt was thencooled to -20° and exposed to 2,6,6-trimethylcyclohex-2-en-1-one (2.28)dissolved in diethyl ether (5 ml).

After complete addition, the reaction mixture was stirred at roomtemperature for 1 hr, quenched with acetic acid (10 ml; at 20° C) andstirred a further 16 hr at room temperature (10 min is sufficient).Dilution with brine and more ether yielded 1-ethoxy[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane(5.5g) on removal of the solvents "in vacuo".

EXAMPLE 41-(2,6,6-Trimethyl-3-acetoxycyclohexen-1-yl)3-methyl-4-penten-1-yn-3-ol

The compound1-ethoxy-[1-(2,6,6-trimethyl-1-hydroxy-2-cyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-oxy]ethane(9.5) in acetic acid (40 ml) was heated at 55° for 11/2 hr and thentaken to dryness "in vacuo" (45° at .5 mmHg), dissolved in hexane, andchromatographed on silica gel (400 g). Elution with hexane-ethermixtures (4:1 parts by volume and 3:1 parts by volume 500 ml cuts, 2liters) yielded1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-ol(4.3g) bp 165° (0.09 mmHg).

EXAMPLE 51-(2,6,6-Trimethyl-3-oxocyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-yne

The compound1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)-3-methyl-4-penten-1-yn-3-ol(4.1 g) dissolved in methanol (15 ml) was treated with a solution ofpotassium hydroxide (1.5 g) in water (5 ml) and left at room temperaturefor 3 hr.

Water was added and the organic material were extracted into ether.Removal of the solvents "in vacuo" yielded the diol i.e.,1-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-yne(3.45 g).

The diol (3.4 g) was dissolved in dichloromethane (20 ml) and added to amixture of chromium trioxide (3 g), pyridine (6g) in dichloromethane(100 ml) at 10° C. The mixture was stirred at room temperature for 2 hrand then worked by the addition of ether filtration of solids andevaporation of solvent to yield1-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-ynecontaminated by starting material. Chromatography on silica gel (150 g)yielded the pure1-(2,6,6-trimethyl-3-acetoxycyclohexen-1-yl)3-methyl-4-penten-1-yn-3-ol(2.7 g) on elution with 30% by volume and 40 % by volume ether-hexanemixtures; bp 160°-165° (0.01 mmHg).

EXAMPLE 6 2,2-Dimethyl-5-oxaheptenoic acid methyl ester

A solution of n-butyllithium in hexane (224 ml; 2.2M) was added totetrahydrofuran (THF, 300 ml) at -60° followed by diiospropylamine (52g) and this mixture was then warmed to room temperature stirred for 5min and then cooled to -72° C. Methylisobutyrate (50 g) was then slowlyadded and the mixture was stirred for 11/2 hr at -70° C. Freshlydistilled ethyl vinyl ketone (42 g) in THF (60 ml) was added to theabove mixture over 10 min and the mixture was then stirred for a further1/2 hr at -60° C and subsequently at room temperature for 2 hr.

After this time the reaction was quenched with aqueous acetic acid andbrine (Ph˜9) and extracted with ether. The ether layer was washed with asaturated brine solution, dried over anhydrous magnesium sulfate andthen concentrated "in vacuo", Distillation of the residue (˜90g) througha 6 inch vacuum jacketed vigreaux column yielded the pure ketoester2,2-dimethyl 5-oxaheptenoic acid methyl ester (81 g) bp 65°-66°.

EXAMPLE 7 2,6,6-Trimethylcyclohexen-1,3-dione

Sodium hydride (15.4 g); 57% by weight dispersion in oil) was washedwith hexane treated with ether (350 ml) and 2,2-dimethyl-5-oxaheptanoicacid methyl ester; (62 g) and heated at reflux (mechanical stirreressential) for 3 hr (methanol; 1/2 ml added to initiate the reaction).The whole reaction mixture set to a solid paste and was cooled in iceand treated with water. The ether layer was washed twice with more waterand the combined aqueous extracts were reextracted with ether. Removalof the ether "in vacuo" yielded the neutral material (2.5 g) which wasdiscarded. The aqueous extract was acidified with ice cold sulfuric acid(6M to pH˜1) and the organic materials were isolated with ether. Removalof the solvents "in vacuo" gave the diketone2,6,6-trimethylcyclohexen-1,3-dione, ˜50g) as a solid. This material wasdigested with cold (-10° to -0°) isopropyl ether (100 ml) and filteredto furnish 2,6,6-trimethylcyclohexen-1,3-dione (43.6g) mp 115°-116° C.

EXAMPLE 8 2,6,6-Trimethyl-3-isobutoxycyclohex-2-en-1-one

The compound 2,6,6-trimethylcyclohexen-1,3-dione (43.6 g) was added to amixture of benzene (250 ml), isobutanol (50 ml) and PTSA (500 mg) andheated under reflux for 3 hr in conjunction with a Dean and Stark waterseparator. The reaction was then cooled to room temperature, washed withaqueous sodium carbonate solution and brine and taken to dryness "invacuo". Distillation of residue through a 6 inch vacuum jacketedvigreaux column yielded pure 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1one (54.6 g) bp 104°-107°.

EXAMPLE 95(2,6,6-Trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol

The acetal compound,1-ethoxy-1-(3-methyl-4-trans-penten-1-yn-1-oxy)ethane (18.6 g) wasdissolved in ether (100 ml), cooled to -60° and treated with ann-butyllithium solution (52.5 ml, 2.2 M in hexane) and then stirred atroom temperature for 15 min. This clear, pale yellow colored solutionwas then cooled to -10°, exposed to the enol ether2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1-one (21 g) dissolved in ether(50 ml), warmed to room temperature and stirred 1 hr more. Dilution withbrine and extraction into ether yielded5(2,6,6-trimethyl-3-oxocyclohexene-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol(37 g) which was then dissolved in acetone (140 ml), added to diluteaqueous sulfuric acid (5% by weight 75 ml) and left at room temperaturefor 16 hr (6-8 hr is sufficient). Most of the acetone was then removed"in vacuo" and the residue was quenched with brine and extracted intoether. Removal of the solvents yielded5(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-trans-penten4-yn-1-ol as yellow crystals which on crystallization from acetone-water(1:1 parts by volume) gave5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol(20.5 g) m.p. 102°-105° C.

EXAMPLE 10 Preparation of1-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-yne

The mixed acetal 1-ethoxy-1-[3-methyl-4-penten-1-yn-3-oxy]ethane (38 g)dissolved in ether (200 ml) was converted to the lithium salt withn-butyllithium (103 ml, 2.2M hexane) as in Example 9. Addition of theketone 2,6,6-trimethyl-3-isobutoxy-cyclohex-2-en-1-one (35.9 g) in ether(100 ml) and proceeding as before yielded the crude adduct which wasdissolved in acetic acid (150 ml) and heated at 60° C for 1 hr. Thesolvents were removed "in vacuo" and the residue was distilled with aKugel Rohr to furnish pure1-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-yne(33.5 g) bp 150°-165° C (0.03 mmHg).

EXAMPLE 115-(2,6,6-Trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-penten-4-yne-1-triphenylphosphoniumbromide

The alcohol,1-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-hydroxy-3-methyl-4-penten-1-yne(450 mg) was dissolved in ether (15 ml), treated with pyridine (1 drop)and exposed to phosphorous tribromide (550 mg) in ether (2 ml) at 0° Cand then stirred a further 15 min at room temperature. Extraction of theether with water and aqueous sodium carbonate solution (10% by weight)yielded the bromide,5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-penten-4-yne-1-bromide(˜500 mg) as a mixture of cis and trans isomers. This material wasdissolved in ethyl acetate (0.5 ml) and added to triphenylphosphine (600mg) dissolved in more ethyl acetate (1.5 ml) and heated to 35° C andleft at room temperature for 3 hr. Ether was added and the solids wereseparated by decantation to yield the5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-penten-4-yne-1-triphenylphosphoniumbromide (800 mg).

EXAMPLE 12 Preparation of1,18-Bis-(2,6,6-trimethyl-4-oxo-1-cyclohexen-1-yl)-3,7,12,16-tetramethyl-3,5,7,11,13,15-octadecahexaene-1,9,17-triyne

The salt from5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-penten-4-yne-1-triphenylphosphoniumbromide (612 mg) was added to 2,7-dimethylocta-2,6-dien-4-yne-1,8-diol(81 mg) dissolved in methanol (5 ml) and cooled to 0° C.

The solution of sodium methoxide (60 mg) in methanol (1 ml) was thenadded and after stirring 20 min the reaction products were extractedwith a mixture of brine and hexane. Removal of the organic solvents "invacuo" yielded products, i.e.,1,18-bis-(2,6,6-trimethyl-4-oxo-1-cyclohexen-1-yl)-3,7,12,16-tetramethyl-3,5,7,11,13,15-octadecahexane-1,9,17-triyne,and1-(2,6,6-trimethyl-4-oxo-1-cyclohexen-1-yl)-3,7,12-trimethyl-3,5,7,11-tridecatetra-1,9-diyn-1-al(320 mg) which was chromatographed on silica gel (35 g). Elution with20% by volume ether and 80% by volume hexane mixture yielded1-(2,6,6-trimethyl-4-oxo-1-cyclohexen-1-yl)-3,7,12-trimethyl-3,5,7,11-tridecatetra-1,9-diyn-1-al,a first product.

Further elution of the column with 30% by volume and 40% by volumeether-hexane mixtures yielded the 1,18-bis(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-3,7,12,16-tetramethyl-3,5,7,11,13,15-octadecahexaene-1,9,17triyne which after crystallization from a hexane-ether mixture had mp95°-100° C.

EXAMPLE 135-(2,6,6-Trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-trans,trans-pentadiene-1-ol

The acetylenic ketone5(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol(4.6 g) dissolved in toluene (80 ml) containing anhydrous potassiumcarbonate (1.2 g) and Lindlar catalyst (700 mg) was hydrogenated at roomtemperature and pressure. A rapid uptake of hydrogen was observed and nonoticeable break in the curve was seen and the reaction was stoppedafter 3 hr when 616 ml of hydrogen had been consumed (21° C at 760mmHg).

The solids were filtered off and the solvents removed "in vacuo" toyield a crude product which contained starting material, over-reducedproducts5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-trans,trans-pentadien-1-ol.

Chromatography on silica gel (400 g) yielded5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-trans,trans-pentadien-1-olon elution with a 75% by volume ether-25% by volume hexane mixture (3.35g).

EXAMPLE 145-(2,6,6-Trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphoniumbromide

The alcohol5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-trans,trans-pentadien-1-ol(3.2 g) in ether (25 ml) was cooled to -60° C, treated with PBr₃ (2.5ml) dissolved in more ether (10 ml) and then warmed to room temperatureover 5 min. Water was added carefully and the organic materials wereisolated with ether. Removal of the solvents "in vacuo" yielded5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-pentadien-1-bromide(3.2 g). This bromide in benzene (15 ml) was exposed totriphenylphosphine (3.5 g) in more benzene (10 ml) and then heated toreflux, cooled and treated with ether (50 ml). The supernatant liquidwas decanted off and the residue was dried to yield the5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphoniumbromide (5.3 g) as a glass.

EXAMPLE 15 Canthaxanthin

The crude salt5-(2,6,6-trimethyl-3-oxocyclohexen-1-yl)-3-methyl,2,4-pentadien-1-triphenylphosphoniumbromide (5.3 g) dissolved in dichloromethane (40 ml) containing2,7-dimethyl-2,4,6-octatriene-1,8-dial. (650 mg) prepared from sodium(285 mg) and methanol (3 ml) and stirred for 1 hr at -10° C.

Dilution with more dichloromethane and extraction with brine yielded thecrude product (5.0 g.) on removal of the solvent "in vacuo". Thisresidue was chromatographed on silica gel (200 g), made up in benzene,yielding the carotenoid fraction (2.1 g) on elution with ethylacetate-benzene mixtures (10% and 20%). Crystallization from methanolyielded canthaxanthin (1.35 g) mp 205°-207° C. The mother liquormaterial (˜ 700 mg) was heated at reflux in water (25 ml) for 16 hr,extracted with dichloromethane and then crystallized from methanol togive more canthaxanthin (400 mg) mp 205°-208° C; a second cycle forthese mother liquors gave a further amount (50 mg) mp 109-202.

EXAMPLE 16 2,5,5-trimethyl-3-isobutyoxycyclopent-2-en-1-one

390 mls. of tetrahydrofuran was placed in a liter flask, cooled to -70°C. and placed under an Argon atmosphere. Add to this 326 mls. of 2.3 M nBuLi and then 84 gms. diisopropyl amine. Stir the solution for 20minutes at -70° C. and then warm to 0° C. with an ice bath. In aseparate 2 liter flask dissolve 55 grams of2-methyl-3-isobutoxycyclopent-2-en-1-one to which the above lithiumdiisopropylamide and methyl iodide are added consecutely in thefollowing manner:

    ______________________________________                                        Amt. of Base Solution                                                                      Amt. of methyliodide                                                                         Mole equivalent                                   ______________________________________                                        365 ml.      46.2 gm.       1.0                                               255 ml.      32.4 gm.       0.7                                               109 ml.      13.8 gm.       0.3                                                73 ml.      9.2 gm.        0.2                                               36.4 ml.     4.62 gm.       0.1                                               ______________________________________                                    

The base is added at -70° C. and then the methyl iodide at -70° C. Thereaction mixture is warmed to room temperature and stirred for 15minutes before the next addition of base and methyl iodide.

The mixture is worked up after the five additions by dilution with etherand washing with brine. The ether is dried and removed under vacuum toyield approximately 60 grams of crude product. The product is flaskdistilled (86° C. at 5 mm) and then fractionally distilled with aGoodloe column to remove the traces of mono and trialkylated material(b.p. approximately 212° C. at 320 mm). Final yield of2,5,5-trimethyl-3-isobutoxycyclopent-2-en-1-one is 47.2 grams (79%).

EXAMPLE 175-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol

36.8 grams of 2,5,5-trimethyl-3-isobutoxycyclopent-2-en-1-one isdissolved in approximately 200 mls. of anhydrous ether. The mixture isdegassed at -70° C. and placed under an inert atmosphere. To this 137mls. of 1.6 M n-butyl lithium in hexane is added at -70° C. and thereaction mixture is stirred for 10 minutes at -70° C. and then warmed toroom temperature. The 29 gms. dialkylated enol ether5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol is dissolved in approximately 50 mls. of anhydrous ether andadded slowly at room temperature. The reaction is stirred for one hourand then diluted with ether. The ether is washed with brine, dried overMgSO₄ and removed under vacuum to yield 59.4 grams of crude product.

The product is then dissolved in 200 mls. of acetone and 100 mls. of 2 NH₂ SO₄ (aqueous). The mixture is stirred under argon for 90 minutes. Theacetone was removed under vacuum and the residue was dissolved in ether,washed with brine, dried over MgSO₄ and filtered through celite. Theether was removed to yield the crude alcohol (33.2 grams, approximately103% contains some 1 inch Pentol). Recrystallization from isopropylether yielded 25.8 grams of5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-penten-4-yn-1-ol(79.5%) of alcohol (m.p. 66°-68° C.).

EXAMPLE 185-(2,5,5-trimethyl-3-oxycyclopenten-1-yl)-3-methyl-2-trans-4-cis-pentadien-1-ol

To 50 mls. of ethyl acetate was added 3.0 grams of Lindlar catalyst, 5.0grams of KCO₃ and 0.009 mls. of quinoline. The mixture was stirred underH₂ gas until no more hydrogen was absorbed. Then 4.4 grams of the5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-penten-4-yn-1-olwere added and hydrogenated (1 atmosphere, 21° C., 484 mls. of H₂ abs.1.01 m. equiv.). The reaction mixture obtained approximately 10%overreduced material and 5% starting material. The mixture was a yellowoil which contained5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-4-cis-pentadien-1-olas a crude product.

EXAMPLE 195-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphoniumbromide

The 1.64 grams of5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2-trans-4-cis-pentadien-1-olwere dissolved in approximately 15 mls. of anhydrous ether and placed inan argon atmosphere. Then 3.6 mls. of PBr₃ in ether (2 mls. of PBr₃ /20ml. of ether) were added slowly at -60° C. The reaction was stirred at-60° C. for approximately 45 minutes and then washed to roomtemperature. The reaction mixture was diluted with more ether andcarefully quenched with H₂ O. The ether layer was washed with brine anddried with MgSO₄. Benzene was added and the ether was removed leavingthe bromide, i.e.,5-(2,5,5-trimethyl-3-oxo-cyclopenten-1-yl)-3-methyl-2,4-pentadiene-1-bromidein benzene (230 mls.).

To this bromide solution was added 1.95 grams of triphenyl phosphinedissolved in approximately 20 mls. of benzene. The solution was refluxedwith 11/2 hours. The solution was cooled and anhydrous ether was addedprecipitating out5-(2,5,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphoniumbromide.

EXAMPLE 20 2,2'-Dinor-Canthaxanthin

1.3 grams of phosphonium salt5-(2,3,5-trimethyl-3-oxocyclopenten-1-yl)-3-methyl-2,4-pentadien-1-triphenylphosphoniumbromide was dissolved in 20 mls. of methylene chloride. 0.126 grams of2,7-dimethyl-octa-2,4,6-triene-1,8-dial was added and the solution wasbrought to -10° C. under an inert atmosphere. The solution was treatedwith 2.38 mmoles of sodium methoxide (1.1 molar in methanol) and stirredfor 40 minutes at -10° C. The methylene chloride mixture was washed withbrine, dried and the solvent removed under vacuum. The crude product wasrefluxed in water for 16 hours and chromatographed on 140 grams ofsilica gel (ether/hexane was used as the eluding solvents). The desiredfraction was recrystallized from MeOH at -70° C. Final yield of2,2'-dinor-canthaxanthin was 0.140 grams (33.3%) m.p. 226°-299° C.

I claim:
 1. A compound of the formula: ##STR36##